Considerable effort has been devoted to the development of efficient methods for the preparation of enantiomerically pure secondary alcohols due to the significance of these intermediates, e.g., in the manufacture of pharmaceuticals. The catalytic asymmetric reduction of prochiral ketones as a direct route to enantiomeric alcohols is among the most studied and developed strategies. Although intensive studies have focused on the asymmetric hydrogenation which shows excellent enantioselectivities for a wide range of simple ketones, asymmetric hydrosilylation has also attracted much attention because of the mild reaction conditions used and its technical simplicity.
The asymmetric hydrosilylations of prochiral simple ketones mediated by catalysts of rhodium(I) and ruthenium(II), titanium, zinc, tin and copper(I) have been extensively explored. Unfortunately, many of these reactions are routinely conducted at a low substrate-to-ligand ratio (S/L), from 50 to 500. The high cost of catalyst and the low substrate-to-catalyst ratio renders the previous hydrosilylation work commercially unattractive.
More recently, Lipshutz et al, developed a catalyst system formed in situ from CuCl and nonracemic bidentate phosphines (e.g., 3,5-xyl-MeO-BIPHEP or DTBM-SEGPHOS) along with t-BuONa. See Lipshutz et al, Ligand-accelerated, copper-catalyzed asymmetric hydrosilylations of aryl ketones; 123 J. AM. CHEM. SOC. 12917-18 (2001). This system allowed for highly active and enantioselective hydrosilylations of both aryl alkyl and heteroaromatic ketones in the presence of an inexpensive stoichiometric reductant, polymethylhydrosiloxane (PMHS), even at a S/L up to 100,000 which approached the levels achieved in related ruthenium-based asymmetric hydrogenations. The reactions, however, must be performed using standard Schlenk techniques and at low temperatures (e.g., from −50° C. to −78° C.) for maximum enantiomeric excess (ee). Moreover, the presence of a base, such as t-BuONa, was critical for the generation of the active catalyst.
Olivier Riant et al. also recently reported a base-free and air-accelerated CuF2/BINAP/PhSiH3 system for the same transformation which furnished secondary alcohols in moderate to good enantioselectivites under ambient conditions at lower S/L ratios of 100-200. See Sabine Sirol et al., Efficient enantioselective hydrosilylation of ketones catalyzed by air stable copper fluoride-phosphine complexes, 3 ORG. LETT. 4111-13 (2001). Although Riant's system is air-stable and conducted at mild reaction temperatures, the activities, enantioselectivities and substrate scope are not comparable to those described by Lipshutz.
Thus, there is a need for a catalyst system for the process for preparing secondary alcohols that results in high reactivities and enantioselectivities and conducted under mild conditions, normal atmosphere and without the addition of a base. The present invention addresses this need.